Six-Month Strategy for Rifampicin-Resistant Tuberculosis

Key Takeaways

• At the end of treatment and at 76 weeks, successful outcomes were almost identical between groups, and the 6-month strategy met the prespecified noninferiority margin.
• Grade 3 or higher adverse events occurred at similar rates, and anemia attributed to linezolid was the most common serious adverse event.
• The susceptibility-guided strategy was delivered in a pragmatic outpatient-oriented program and included children as well as pregnant or breastfeeding participants.

In South Africa, a 6-month strategy for rifampicin-resistant tuberculosis had an adjusted risk difference of -0.2 percentage points versus the 9-month standard approach in a phase 3 pragmatic randomized trial. The open-label noninferiority study enrolled adults and children 6 years of age or older, including participants who were pregnant or breastfeeding. Treatment took place within South African programmatic care, with regimen selection guided by second-line susceptibility results. The shorter strategy met the prespecified noninferiority criterion without demonstrating superiority.

In the open-label trial, 403 of 432 screened individuals underwent randomization at two urban South African sites, and one randomization error left 202 and 200 participants in the intention-to-treat groups. The 6-month regimen included bedaquiline, linezolid, delamanid, and levofloxacin or clofazimine or both, while the comparator was South Africa’s 9-month standard regimen. In both groups, treatment was adjusted after second-line susceptibility testing, with fluoroquinolone results guiding discontinuation or noninitiation of levofloxacin or clofazimine. Median age was 35 years, 50.9% had HIV coinfection, and the primary efficacy endpoint was successful outcome, defined as cure or treatment completion at the end of treatment and at 76 weeks.

In the noninferiority analysis, successful outcomes occurred in 174 of 202 participants in the trial-strategy group and 172 of 200 in control. The adjusted risk difference was -0.2 percentage points, with a 95% confidence interval of -6.9 to 6.5 and P=0.001 for noninferiority. The prespecified margin was 10 percentage points; treatment failure occurred in 7 versus 10 participants, and recurrence in 10 versus 4. No apparent between-group difference was seen in time to stable negative culture conversion, and the composite efficacy-safety endpoint was 60.9% versus 57.5%.

Grade 3 or higher adverse events during treatment occurred in 31.2% of the trial-strategy group and 37.0% of control, with 10 deaths in each group. Anemia attributed to linezolid was the most common serious adverse event, occurring in 33 versus 29 participants. Most anemia appeared within 8 weeks and was managed with brief linezolid interruptions and packed red-cell transfusion. Peripheral neuropathy leading to permanent linezolid discontinuation occurred in 10 versus 7 participants, and optic neuritis in 7 versus 2. Severe liver-related events occurred in 4 versus 9 participants, asymptomatic corrected QT prolongation above 500 msec in 5 versus 7, and most participants completed 6 months of linezolid at 600 mg.

Care was outpatient when possible, using family- or community-supporter directly observed therapy, pill counts, and return verification, with follow-up visits every 2 weeks initially and then every 4 weeks. Post-treatment visits were monthly for 3 months and then every 3 months to 76 weeks, and no convincing differential effects were seen across subgroups, although power was limited. Fluoroquinolone resistance was identified in 85 participants, and 72 had no later results because cultures were contaminated or did not grow in this single-country trial. Phenotypic bedaquiline susceptibility testing succeeded in 63 isolates, and four baseline bedaquiline-resistant isolates were all in the control group. One control-group child had delamanid-attributed neuropsychiatric reactions, one pregnant participant in the trial-strategy group had recurrent tuberculosis, all pregnancies resulted in singleton live births with one premature delivery, and generalizability beyond similar settings remains uncertain.